2-(3,5-Substituted-2-pyridylalkylamino)-5-oxopyridylmethyl-4-pyrimidones useful as histamine H1 -antagonists

ABSTRACT

Pyridone derivatives useful as histamine H 1  -antagonists are disclosed.

This invention relates to certain pyridone derivatives, a process for their preparation, compositions containing them and their use as histamine H₁ -antagonists.

Histamine, a physiologically active compound endogenous in mammals, exerts its action by interacting with certain sites called receptors. One type of receptor is known as a histamine H₁ -receptor (Ash and Schild, Brit. J. Pharmac. 1966, 27, 427) and the actions of histamine at these receptors are inhibited by drugs commonly called "antihistamines" (histamine H₁ -antagonists) a common example of which is mepyramine. A second type of histamine receptor is known as the H₂ -receptor (Black et al Nature 1972, 236, 385). The actions of histamine at these receptors are not inhibited by mepyramine but are inhibited by burimamide. Compounds which inhibit the actions of histamine at histamine H₂ -receptors are called histamine H₂ -antagonists.

U.S. Pat. No. 4,255,428 describes compounds of formula (1):- ##STR1## in which inter alia Het is a 2-pyridyl group optionally substituted by one or more (which can be the same or different) lower alkyl (preferably methyl), lower alkoxy (preferably methoxy), halogen (preferably chlorine or bromine), amino or hydroxy groups;

Y is methylene; Z is hydrogen ; A is --CH₂ -- and

Het¹ is a pyridyl group substituted by hydroxy.

These compounds are useful as histamine H₂ -antagonists.

A group of compounds has now been discovered which have a relatively higher level of H₁ - to H₂ -antagonist activity. These compounds are useful as histamine H₁ -antagonists, that is, for the treatment of diseases for example bronchial asthma, rhinitis, hayfever and allergic eczema whose symptoms are mediated through the action of histamine at H₁ -receptors.

According to the present invention there is provided compounds of formula (2) :- ##STR2## and pharmaceutically acceptable salts thereof; where R¹ is halogen, nitro, amino (or a pharmaceutically acceptable derivative of the amino group which is convertible in vivo into amino) or C₁₋₄ alkyl;

R² is halogen, nitro, amino (or a pharmaceutically acceptable derivative of the amino group which is convertible in vivo into amino), C₁₋₄ alkyl or C₃₋₄ alkoxy;

R³ is a C₁₋₃ alkylene group; and

R⁴ is a pyridone group in which the nitrogen atom is optionally substituted with a group R⁵, where R⁵ is C₁₋₄ alkyl, hydroxy C₁₋₄ alkyl, C₁₋₄ alkoxy-C₁₋₄ -alkyl, or optionally substituted phenyl-C₁₋₄ alkyl; or is a 2- or 4- C₁₋₄ alkoxy pyridyl group.

R¹ and R² can represent any one of the halogens, fluorine, chlorine, bromine or iodine.

Preferably R¹ is halogen particularly bromine.

R¹ and R² can represent amino or a pharmaceutically acceptable derivative thereof which is convertible in vivo into amino, that is, derivatives which in vivo are hydrolysed or metabolised to a free amino group. Examples include C₁₋₄ alkylamino particularly methylamino and C₁₋₄ alkanoylamino particularly acetamido.

Examples of C₁₋₄ alkyl groups for R¹ and R² are methyl, ethyl, n-propyl, iso-propyl, n-butyl and t-butyl.

Examples of C₃₋₄ alkoxy groups for R² are n-propoxy and n-butoxy.

Preferably R² is either C₁₋₄ alkyl, particularly methyl, or amino.

By way of example R³ can be methylene, 1,2-ethanediyl, or 1,3-propanediyl.

The pyridone group R⁴ has a number of isomers (a) to (f) below:- ##STR3## where R⁶ is hydrogen or a group R⁵ as defined with reference to formula (2). Accordingly reference to pyridone is to be understood to include reference to all these isomers unless the context requires otherwise.

When R⁶ is hydrogen, the pyridone group can also exist as an enol tautomer. This keto-enol tautomerism is represented by the partial structures below:- ##STR4##

So by way of example isomer (d) can exist in two tautomeric forms as follows:- ##STR5##

It will be understood that all these tautomeric forms are within the scope of the present invention.

Preferably the group R⁴ is an isomer of formula (d), that is to say 2-oxopyrid-4-yl.

Compounds of formula (2) where R⁴ is a 2- or 4-C₁₋₄ alkoxy pyridyl group are useful as histamine H₁ -antagonists in their own right or as intermediates for the preparation of the corresponding pyridone.

Examples of such C₁₋₄ alkoxy groups are methoxy, ethoxy and propoxy. Preferably the C₁₋₄ alkoxy group is methoxy.

Examples of C₁₋₄ alkyl groups which R⁵ represents are methyl, ethyl, propyl and butyl. In particular it is methyl or n-butyl.

Examples of hydroxy-C₁₋₄ alkyl groups which R⁵ represents are 2-hydroxyethyl and 3-hydroxypropyl.

Examples of C₁₋₄ alkoxy-C₁₋₄ alkyl groups which R⁵ represents are methoxyethyl, ethoxyethyl, and methoxypropyl.

Examples of the optional substituents on the phenyl moiety of the optionally substituted phenyl C₁₋₄ alkyl group which R⁵ represents are hydroxy, halogen, C₁₋₄ alkoxy, and C₁₋₄ alkyl. Preferably the substituent in the phenyl moiety is in position 4 (that is para) relative to the point of attachment of the phenyl moiety to the C₁₋₄ alkyl group. Thus examples of optionally substituted phenyl C₁₋₄ alkyl groups for R⁵ are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-hydroxybenzyl, 2-(4-hydroxyphenyl)ethyl, 3-(4-hydroxyphenyl)propyl, 4-methoxybenzyl, 2-(4-methoxyphenyl)ethyl, 3-(4-methoxyphenyl)propyl, 4-chlorobenzyl, 2-(4-chlorophenyl)ethyl, 4-methylbenzyl, 2-(4-methylphenyl)ethyl and 3-(4-methylphenyl)propyl. In particular it is 2-(4-hydroxyphenyl)ethyl or 2-(4-methoxyphenyl)ethyl.

Examples of compounds within the scope of this invention are :-

2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[1-methyl-2-oxopyrid-4-ylmethyl]-4-pyrimidone;

2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[1-[H]-2-oxopyrid-4-ylmethyl]-4-pyrimidone;

2-[4-(5-bromo-3-aminopyrid-2-yl)butylamino]-5-[1-n-butyl-2-oxopyrid-4-ylmethyl]-4-pyrimidone;

2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[1-benzyl-2-oxopyrid-4-ylmethyl]-4-pyrimidone;

2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[1-(2-phenylethyl)-2-oxopyrid-4-ylmethyl]-4-pyrimidone;

2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[1-(2-(4-hydroxyphenyl)ethyl)-2-oxopyrid-4-ylmethyl]-4-pyrimidone;

and their pharmaceutically acceptable salts.

The compounds of formula (2) are shown and described as 4-pyrimidones which exist in equilibrium with the corresponding 6-one tautomers. These compounds also exist to a lesser extent as the hydroxy tautomers, and the pyrimidine ring may also exist in the following tautomeric forms : ##STR6##

It will be understood that all these tautomeric forms are within the scope of the present invention.

The compounds of formula (2) form pharmaceutically acceptable salts with pharmaceutically acceptable salt-forming acids. Examples of these acids are hydrochloric, sulphuric, hydrobromic, phosphoric, tartaric, citric, maleic, lactic, 2-hydroxyethanesulphonic, methanesulphonic, toluene-4-sulphonic, ethanedisulphonic, ethanesulphonic and camphorsulphonic acids.

The compounds of this invention can be made by a process which comprises reacting a compound of formula (3):- ##STR7## or a salt thereof, where R⁷ is a group R¹ or a protected amino group , R⁸ is a group R² or a protected amino group and R³ is as defined with reference to formula (2), with a compound of formula (4):- ##STR8## where R⁹ is a group displaceable with amine, and R¹⁰ is pyridyl substituted in position 2 or 4 with a protected hydroxy group or a pyridone group in which the nitrogen atom is substituted with a group R⁵ as defined with reference to formula (2) and thereafter, where necessary, removing any protecting group from a protected amino group in the product so obtained; optionally converting any amino group in the product so obtained into a pharmaceutically acceptable derivative which is convertible in vivo into amino; where R¹⁰ is pyridyl substituted with a protected hydroxy group other than C₁₋₄ alkyl, (and optionally where the protecting group is C₁₋₄ alkyl) removing the protecting group and thereafter optionally converting the compound of formula (2) so obtained into a pharmaceutically acceptable salt.

In the protected amino group R⁷ or R⁸, the protecting group can be any standard amino protecting group which is stable under the reaction conditions. For example it can be C₁₋₄ alkanoyl, benzyl or benzoyl.

These protecting groups can be introduced and removed by standard methods.

Where the protecting group is one which is either not pharmaceutically acceptable or not convertible in vivo into amino then it is removed. Where the protecting group is convertible in vivo into amino then it need not be removed unless the free amino compound is required. Optionally any free amino group is converted into a derivative which is convertible in vivo into a free amino group. This conversion can be carried out by standard methods for example acylation or alkylation.

Examples of groups R⁹ are C₁₋₄ alkylthio (particularly methylthio), benzylthio, chlorine, bromine and nitroamino. Preferably R⁹ is nitroamino.

The reaction can be carried out at an elevated temperature in the absence of a solvent, for example at from 80° to 170° C., preferably from 120° to 140° C., or in a solvent at an elevated temperature, for example at the reflux temperature of the reaction mixture. The choice of solvent is affected by solubility characteristics of the reactants and the nature of R⁹. Preferably the solvent is pyridine, a picoline or mixture of picolines, a C₁₋₄ alkanol, preferably ethanol or 1-propanol, 1,2-ethanediol, a ketone, for example acetone or 2-butanone, a high boiling alkoxyaryl ether for example anisole, or a polar aprotic solvent, for example dimethylformamide, dimethylacetamide, dimethylsulphoxide, hexamethylphosphoramide, sulpholane, acetonitrile or nitromethane.

The use of protecting groups for the protection of hydroxy is discussed in J. F. McOmie, Protective Groups in Organic Chemistry, 1973, Plenum Press, IBSN 0-306-30717-0. Examples of hydroxy protecting groups are methoxymethyl, methylthiomethyl, tetrahydropyranyl, arylmethyl, for example benzyl, C₁₋₄ alkyl, for example methyl, and alkanoyl, for example formyl or acetyl.

These protecting groups can be removed by standard methods, for example where the protecting group is alkanoyl or C₁₋₄ alkyl, by acid hydrolysis.

Pharmaceutically acceptable salts of compounds of formula (2) can be prepared by standard methods, for example by reacting a solution of the compound of formula (2) with a solution of the acid.

Compounds of formula (3) can be prepared as described or by analogy with methods described in European Pat. Applications Nos. 0068833 and 0068834.

Compounds of formula (3) where one of R¹ and R² is amino and neither is nitro can also be prepared as follows:-

A compound of formula (5) or (6):- ##STR9## where W is halogen, C₁₋₄ alkyl or C₃₋₄ alkoxy and X is halogen or C₁₋₄ alkyl, is reacted with hydrazine and a transition metal catalyst to produce a compound of formula (7) or (8):- ##STR10## where R³, W and X are as defined with reference to formula (5) and (6) and thereafter reacting the compound of formula (7) or (8) so obtained with more hydrazine and Raney nickel.

This reaction is carried out at a moderate temperature, for example from 5° C. to about 70° C. and preferably from about 10° C. to room temperature.

The first hydrazine reduction to prepare compounds of formula (7) and (8) can be carried out using hydrogenation catalysts which are milder than Raney nickel.

An example of a mild catalyst for this step is palladium on an inert support (in particular palladium on charcoal). The temperature at which the reaction is carried out depends on the catalyst. Where a mild catalyst is employed, higher temperatures for example from 55°-70° C. may be employed. With a more powerful catalyst, for example Raney nickel, the temperature does not in practice exceed 55° C.

Preferably the reaction is carried out at from 5° C. to room temperature regardless of the catalyst.

After the first step has been carried out, the compound of formula (7) or (8) can be recovered by removing the catalyst (e.g. by filtration) and evaporating the solvent. The second step can then be carried out by redissolving the compound of formula (7) or (8) so obtained in the same or a different solvent and reacting with Raney nickel and more hydrazine.

Preferably the reaction is carried out as a concerted process, that is by reacting the compound of formula (5) or (6) with sufficient hydrazine and a catalyst to form a compound of formula (7) or (8) in situ, where the catalyst for the first step is not Raney nickel, removing the catalyst (e.g. by filtration) and then adding Raney nickel and sufficient hydrazine to convert the compound of formula (7) or (8) into the corresponding compound of formula (3).

The reaction of the first or second step can be carried out in the presence of a solvent the choice of which is not critical to the success of the reaction provided that it is substantially inert to the reagents and product. Examples of solvents for use in this process include C₁₋₆ alkanols in particular methanol and ethanol.

The time for which the reaction in each step is allowed to proceed depends upon the nature of reagents, the temperature at which it is carried out and in the first step, the catalyst. The progress of the reaction can be monitored by standard techniques for example thin layer chromatography, and when the reaction has finished, the product can be isolated by standard techniques, for example removing the catalyst by filtration and evaporating the solvent.

Compounds of formula (5) and (6) can be made by analogy with known processes.

The compounds of formula (4) where R¹⁰ is pyridyl substituted with a protected hydroxy group are described in U.S. Pat. No. 4,255,428. Compounds of formula (4) where R¹⁰ is a 2-pyridone where the nitrogen atom is substituted with a group R⁵ can be prepared in an analogous way.

The compounds of the formula (4) where R⁹ is nitroamino can be prepared by the reaction of a compound of the formula (9) :- ##STR11## where R¹⁰ is as defined with reference to formula (4) and R¹¹ is C₁₋₄ alkyl, with nitroguanidine.

The compound of the formula (4) wherein R⁹ is C₁₋₄ alkylthio or benzylthio can be prepared by the reaction of a compound of the formula (9) with thiourea followed by alkylation or benzylation.

The compounds of the formula (4) wherein R⁹ is chloro or bromo may be prepared by the reaction of a compound of the formula (9) with guanidine, followed by diazotisation in hydrochloric acid in the presence of cuprous chloride and copper, or by diazotisation in hydrobromic acid in the presence of cuprous bromide and copper.

Preferably the reactions of the compound of the formula (9) with nitroguanidine, thiourea and guanidine are carried out in the presence of a base, for example, an alkali metal C₁₋₄ alkoxide, preferably sodium methoxide or sodium ethoxide, an alkali metal carbonate or hydroxide, preferably potassium carbonate or sodium hydroxide, sodium hydride or a quaternary ammonium hydroxide, for example benzyltrimethylammonium hydroxide. Preferably this reaction is carried out at an elevated temperature, for example the reflux temperature of the solvent mixture. Preferably the solvent is a C₁₋₄ alkanol, for example ethanol, an aqueous C₁₋₄ alkanol, a ketone, for example 2-butanone, or a polar aprotic solvent, for example dimethylformamide. The compound of the formula (9) may also be used in the form of a hemiacetal, for example of a C₁₋₄ alkanol.

Compounds of the formula (4) with other values of R⁹ may be prepared in conventional manner.

The compounds of the formula (9) can be prepared in a conventional manner, for example by analogy with the processes disclosed in U.S. Pat. No. 4,154,834.

The compounds of the formula (9) can also be prepared for example by the reaction of a compound of the formula (10) :- ##STR12## wherein R¹⁰ and R¹¹ are as defined with reference to formula (9), with a formylating agent, for example a C₁₋₄ alkyl formate particularly ethyl formate, in the presence of a strong base. Suitably the base is sodium hydride in 1,2-dimethoxyethane or tetrahydrofuran. An alternative base can be sodium in ether.

Compounds of formula (2) can also be prepared by reacting a guanidine of formula (11):- ##STR13## where R¹, R² and R³ are as defined with reference to formula (2) with a compound of formula (12) :- ##STR14## where R⁴ is as defined with reference to formula (2) and R¹² is C₁₋₄ alkyl (particularly ethyl) benzyl or phenyl.

The reaction can be carried out by heating the guanidine of formula (11) with the compound of formula (12) optionally in a solvent for example an alcohol corresponding to the ester function in the compound of formula (12) that is R¹² OH, at an elevated temperature, preferably in the presence of a base in particular the sodium alkoxide NaOR¹² corresponding to the ester function of the compound of formula (12).

The guanidines of formula (11) can be prepared by reacting an amine of formula (3) with a compound of formula (13) :- ##STR15## where R¹³ is a leaving group for example methylthio.

The histamine H₁ -antagonist activity of the compounds of formula (2) can be demonstrated in vitro in the guinea pig ileum test. In this test an isolated portion of the guinea pig ileum is secured under tension (500 mg) between an anchorage and a transducer in a 10 ml tissue bath and immersed in magnesium free Tyrode solution with constant aeration at a temperature of 30° C. The output from the transducer is amplified. The amplified output is in turn fed to a flat bed recorder. Measured amounts of histamine are added to the tissue bath so that the histamine concentration increases step-wise until the force of the contraction reaches a maximum. The tissue bath is washed out and filled with fresh magnesium free Tyrode solution containing compound under test. The solution is left in contact with the tissue for 8 min. and measured amounts of histamine are added again until a maximum contraction is recorded. The assay is repeated with increasing concentrations of test compound and the dose of histamine giving 50% of maximum contraction is noted. A dose ratio (DR) was calculated by comparing the concentrations of histamine required to produce 50% maximum response in the absence and in the presence of the antagonist. A plot of Log DR-1 against Log D (the concentration of compound under test) is made and the point of intersection with the Log (DR-1) ordinate is taken as the measure of the activity (pA₂ value). The compounds of Examples 1 to 3 have pA₂ values greater than 8.

The histamine H₂ -antagonist activity of the compounds of formula (2) can be determined in vitro in the guinea pig atrium test. In this test a spontaneously beating isolated portion of the guinea pig right atrium is secured under tension (300 mg) between an anchorage and a transducer in a 15 ml tissue bath and immersed in McEwens solution with constant aeration at a temperature of 37° C. The output from the transducer is amplified. Output is in turn fed to a flat bed recorder. Measured amounts of histamine are added to the tissue bath so that the histamine concentration increases step-wise until the rate of beating reaches a maximum. The tissue bath is washed out and filled with fresh McEwens solution containing compound under test. The solution is left in contact with the tissue for 60 min. and measured amounts of histamine are added again until a maximum rate is recorded. The assay is repeated with increasing concentrations of test compound and the dose of histamine giving 50% of maximum rate is noted. A dose ratio (DR) was calculated by comparing the concentrations of histamine required to produce 50% maximum response in the absence and in the presence of the antagonist. A plot of Log DR-1 against Log D (the concentration of compound under test) is made and the point of intersection with the Log (DR-1) ordinate is taken as the measure of the activity (pA₂ value). The compounds of Examples 1 to 3 have pA₂ values of less than 5. Thus the difference in pA₂ values is greater than 3.

The activity of compounds of formula (2) as histamine H₁ -antagonists can be demonstrated in vivo by the inhibition of histamine induced bronchoconstriction. Guinea pigs of either sex are anaesthetised by intraperitoneal injection of sodium pentobarbitone, 90 mg/kg. The trachea is cannulated. The animal is respired artificially with a fixed volume of air just adequate to inflate the lungs. The pressure needed to inflate the lungs is monitored from the respiratory system using a low pressure transducer. Intravenous injection of histamine causes dose-dependent increases in the pressure to inflate the lungs reflecting the bronchoconstrictor action of histamine. Responses to histamine can be antagonised using histamine H₁ -receptor antagonists.

Dose-response curves to histamine are established at 20, 40, 80, 160 and 320 nmols/kg. Antagonists are then administered by intravenous injection and 5 minutes later a new histamine dose-response curve is established increasing the doses of histamine as necessary. The effect of the antagonist can be quantified by the displacement, to the right, of the histamine dose-response curve, expressed as a dose-ratio. A series of doses of antagonists may be given to each animal allowing calculation of dose-ratios for each dose of antagonist.

The activity of the compounds of formula (2) as histamine H₂ -antagonists can be determined in vivo by the inhibition of histamine-stimulated secretion of gastric acid from the lumen-perfused stomachs of rats anaesthetised with urethane. This procedure is referred to in Ash and Schild, Brit. J. Pharmac. Chemother., 27, 247 (1966).

In order to use the compounds of the invention as histamine H₁ -antagonists, they can be formulated as pharmaceutical compositions in accordance with standard pharmaceutical procedure.

The invention also includes pharmaceutical compositions comprising a compound of formula (2) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Compounds of formula (2) and their pharmaceutically acceptable salts can be administered topically or systemically.

Topical formulations for administration to the skin include lotions and creams. Topical formulations for administration to the respiratory tract include solutions for application via a nebulizer or as an aerosol, or a microfine insufflatable powder. The active ingredient in an insufflatable powder has a small particle size i.e. less than 50 microns and preferably less than 10 microns. The active material is co-presented with a solid carrier for example lactose which has a particle size of less than 50 microns.

Systemic administration can be achieved by rectal, oral or parenteral administration. A typical suppository formulation comprises the active compound with a binding agent and/or lubricating agent for example gelatine or cocoa butter or other low melting vegetable waxes or fats. Typical parenteral compositions consist of a solution or suspension of the active material in a sterile aqueous carrier of parenterally acceptable oil.

Compounds of formula (2) which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation generally consists of a suspension or solution of the compound in a liquid carrier for example ethanol, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a capsule, the solid in granular form optionally with a binding agent is encased in a gelatin shell. Where the composition is in the form of a tablet, any suitable pharmaceutical carrier routinely used for preparing solid formulations can be used. Examples of such carriers include magnesium stearate, starch, lactose, glucose, sucrose, and cellulose. Preferably the composition is in unit dose form for example a tablet, capsule or metered aerosol.

Where appropriate, bronchodilators and anti-asthmatics for example sympathomimetic amines particularly isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives particularly theophylline and aminophylline; and corticosteroids particularly prednisolone and adrenal stimulants particularly ACTH can be included.

Each dosage unit for oral administration contains preferably from 1 to 200 mg of a compound of formula (2) or a pharmaceutically acceptable salt thereof calculated as the free base.

The invention also provides a method of blocking histamine H₁ -receptors which comprises administering to a subject an effective amount to block said receptors of a compound of formula (2) or a pharmaceutically acceptable salt thereof.

The compounds of formula (2) and their pharmaceutically acceptable salts will normally be administered to a subject in a pharmaceutical composition as described above, for the treatment of rhinitis, hayfever, bronchial asthma or allergic eczema. An adult subject will receive an oral dose of between 15 mg and 400 mg and preferably between 15 mg and 200 mg or an intravenous, subcutaneous or intramuscular dose of between 1 mg and 50 mg, and preferably between 1 mg and 10 mg of a compound of formula (2) or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.

The following Examples illustrate the invention.

EXAMPLE 1

4-(5-Bromo-3-methylpyrid-2-yl)butylamine (0.445 gm.) and 2-nitroamino-5-(1-methyl-2-oxo-pyrid-4-ylmethyl)-4-pyrimidone (0.45 ml) were refluxed in pyridine (2 ml) for 9.5 hrs. Pyridine was removed in vacuo, the residue was re-evaporated with n-propanol (2×20 ml) giving a brown oil (1.01 gm) which was dissolved in ethanol (40 ml) and heated with charcoal (0.1 gm) and the ethanol removed in vacuo. The resulting yellow oil was twice crystallised from acetonitrile-water (9:1) to give 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(1-methyl-2-oxo-pyrid-4-yl-methyl)-4-pyrimidone (0.38 gm) m.p. 203°-204° C.

    C.sub.21 H.sub.24 BrN.sub.5 O.sub.2

Requires C 55.03, H 5.23, N 15.27, Br 17.43;

Found C 54.91, H 5.13, N 15.24, Br 17.89.

EXAMPLE 2

4-(5-Bromo-3-methylpyrid-2-yl)butylamine (0.71 gm) and 2-nitroamino-5-(1-benzyl-2-oxo-pyrid-4-ylmethyl)-4-pyrimidone (1.0 gm) were refluxed in pyridine (3 ml) for 8 hrs., an extra 0.13 gm of the amine was added and reaction was refluxed for a further 5.5 hrs. The pyridine was removed in vacuo, the residue was re-evaporated with n-propanol (2×40 ml). The residue was dissolved in warm ethanol (10 ml) ether added and on cooling a white solid was obtained which was recrystallised from acetonitrile-water (9:1) to give 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(1-benzyl-2-oxo-pyrid-4-ylmethyl)4-pyrimidone (1.18 gm) m.p. 140°-144° C.

    C.sub.27 H.sub.28 BrN.sub.5 O.sub.2

Requires C 60.67, H 5.28, N 13.10, Br 14.95;

Found C 61.14, H 5.27, N 13.29, Br 14.66.

EXAMPLE 3

(a) A mixture of concentrated sulphuric acid (35 ml) and nitric acid (35 ml) was added dropwise with stirring to a chilled (5° C.) solution of 2-amino-5-bromopyridine (50.3 g) in concentrated sulphuric acid (240 ml) maintaining the temperature of the reaction mixture at 5°-6° C. throughout the addition. When the addition was complete, the reaction mixture was stirred for a further 1.0 hr. at 5°-8° C. and then warmed to 30° C. and allowed to stand for ca 18 hr.

Further concentrated nitric acid (35 ml) was added portionwise to the reaction mixture with stirring while maintaining the temperature at 30°-40° C. A portion (50 ml) of the solution was poured into hot (ca 70° C.) water (100 ml) with rapid stirring and this mixture was heated to 120° C. Gas evolved. When the evolution of gas ceased further portions (75 ml) of the reaction mixture were added maintaining the temperature at 120° C. When the additions were completed, the solution obtained was poured into ice (1 kg) and chilled in a salt/ice bath. Fine orange crystals formed which were removed by filtration and recrystallised from dimethylformamide/water to give 2-hydroxy-3-nitro-5-bromopyridine (23.5 g) m.p. 240°-243° C.

(b) A solution of 2-hydroxy-3-nitro-5-bromopyridine (23.4 g) in phosphoryl chloride (16 ml) was heated under reflux for 2.5 hr. The reaction mixture was poured into ice/water and a brown solid was produced which was removed by filtration. The solid was dissolved in chloroform, dried (MgSO₄) and decolourised by heating with charcoal for 30 min. The solvent was evaporated from the decolourised solution to yield a yellow solid (24.0 g) which was recrystallised from ether/petroleum ether (40°-60° C.) to yield 2-chloro-3-nitro-5-bromopyridine (19.4 g) m.p. 66°-68° C.

(c) A solution of 2-(2-cyanoethyl)malonic acid diethyl ester (24.2 g) in tetrahydrofuran (15 ml) was added to a suspension of sodium hydride (2.45 g) in tetrahydrofuran (30 ml) at 20° C. under nitrogen. To this was added 2-chloro-3-nitro-5-bromopyridine (22 g) and the mixture so obtained was heated to 93°-95° C. A small amount of tetrahydrofuran was allowed to distil off. The mixture was heated under reflux for 2.5 hr. The reaction mixture was poured into water and neutralised to pH 7 with concentrated hydrochloric acid. The aqueous phase was extracted with chloroform, dried (MgSO₄) decolourised with charcoal and filtered through a silica column. The chloroform eluant was evaporated to yield an oil which slowly crystallised. The crystals were washed in petroleum ether (40°-60° C.) and dried to yield 4-(5-bromo-3-nitropyrid-2-yl)-4,4-bis(carbethoxy)butyronitrile (28 g) m.p. 58°-62° C.

(d) 4-(5-Bromo-3-nitropyrid-2-yl)-4,4-bis(carbethoxy)butyronitrile (21.8 g) was added to a mixture of aqueous sodium hydroxide solution (1M, 263.6 ml) and methanol (635 ml). The mixture so obtained was stirred for 18 hr. The mixture was acidified to pH 1.5 by addition of concentrated hydrochloric acid and heated at 50° C. for 4.75 hr. The solution was neutralised to pH 7 with sodium hydroxide solution and the methanol removed by distillation. The aqueous solution remaining was extracted with chloroform to give an oil (11.2 g) which was chromatographed on a silica column with chloroform to give 5-bromo-3-nitro-2-(3-cyanopropyl) pyridine (9.6 g) as a yellow solid m.p. 73°-76° C.

(e) Raney nickel moist with ethanol (34 g) was added to a suspension of finely divided 5-bromo-3-nitro-2-(3-cyanopropyl)pyridine (8.4 g) in ethanol (350 ml) under nitrogen. The mixture was cooled (10° C.) and a solution of hydrazine hydrate (2.34 ml) in ethanol (10 ml) was added maintaining the reaction temperature between 12°-15° C. The reaction mixture was allowed to warm to room temperature with constant stirring and hydrazine hydrate (15.5 ml) was added in portions (2.3 ml) in ethanol (3 ml) at regular intervals over 46 hr. Before each addition the reaction mixture was cooled to 15° C. After 23 hr. more Raney nickel (6 g) was added. The reaction was stopped after 47 hr. The catalyst was removed by filtering the reaction mixture through a pad of diatomaceous earth. Evaporation of the solvent yielded an oil (7.9 g) which was chromatographed on a silica column eluting with ethyl acetate/ethanol/0.880 ammonia 15:10:2 to give 3-amino-5-bromo-2-(4-aminobutyl)pyridine (4.0 g) as an oil.

(f) 4-[5-Bromo-3-aminopyrid-2-yl)butylamine (0.5 g) and 2-nitroamino-5-(1-n-butyl-2-oxo-pyrid-4-ylmethyl)-4-pyrimidone (0.65 g) were refluxed in pyridine (2 ml) for 22 hours. The pyridine was removed in vacuo and the residue was reconcentrated with n-propanol (2×30 ml) to give an oil (1.08 g). This oil was chromatographed on a silica column eluted with ethyl acetate/ethanol/0.88 ammonia (15:10:2) to give a brown oil (0.87 g) which was twice crystallised from ethanol/ether/water mixture to give 2-[4-(5-bromo-3-aminopyrid-2-yl)-butylamino]-5-(1-n-butyl-2-oxo-pyrid-4-ylmethyl)-4-pyrimidone (0.56 g) m.p. 140°-150° C., shrinks 89°-100° C. (dehydration).

EXAMPLE 4

4-(5-Bromo-3-methylpyrid-2-yl)butylamine (3.0 g) and 2-nitroamino-5-(2-methoxypyrid-4-ylmethyl-4-pyrimidone (3.0 g) were refluxed in pyridine (10 ml) for 20 hours. The pyridine was removed in vacuo and the residue was reconcentrated with n-propanol (2×30 ml) to give an oil (5.88 g) which was crystallised from ethanol/ether/water and then ethanol/ether to give 2-[4-(5-bromo-3-methylpyrid2-yl)butylamino]-5-(2-methoxypyrid-4-ylmethyl)-4-pyrimidone (3.81 g) m.p. 120°-121° C.

EXAMPLE 5

Reaction of 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(2-methoxypyrid-4-ylmethyl)-4-pyrimidone (1.0 g) with ethanolic hydrogen chloride solution under reflux for 27 hours gave a pale yellow oil which crystallised on standing. Trituration with ethanol and recrystallisation twice from a mixture of ethanol/methanol containing a trace of hydrogen chloride gave 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(1-H-2-oxo-pyrid-4-ylmethyl)-4-pyrimidone as the hydrochloride (0.89 g) m.p. 232°-235° C.

EXAMPLE 6

A pharmaceutical composition for oral administration is prepared containing

    ______________________________________                                                                 % by weight                                            ______________________________________                                                   2-[4-(5-bromo-3-methylpyrid-2-yl)-                                                                     55                                                     butylamino]-5-[1-methyl-2-oxopyrid-4-yl-                             A         methyl]-4-pyrimidone                                                           Dibasic calcium phosphate dihydrate                                                                    20                                                     Approved coloring agent 0.5                                                    Polyvinylpyrrolidone    4.0                                                    Microcrystalline Cellulose                                                                             8.0                                                    Maize Starch            8.0                                          B         Sodium glycollate       4.0                                                    Magnesium Stearate      0.5                                          ______________________________________                                    

by mixing together the ingredients A (substituting lactose or microcrystalline cellose for dibasic calcium phosphate dihydrate if desired), adding a concentrated solution of polyvinylpyrrolidone and granulating, drying and screening the dried granules; adding the ingredients B to the dried granules and compressing the mixture into tablets containing 5 mg, 25 mg or 50 mg of the free base.

EXAMPLE 7

A pharmaceutical composition for injectable administration is prepared by forming a solution of 2-[4-(5-bromo-3-methyl-pyrid-2-yl)-butylamino]-5-[1-methyl-2-oxopyrid-4-ylmethyl]-4-pyrimidone hydrochloride salt in sterile water to give a 1 to 5% w/w solution. The solution is clarified by filtration and filled into vials which are sealed and sterilised. A suitable vial contains 2 ml of the solution. 

What is claimed is:
 1. A compound of formula (2) ##STR16## or a pharmaceutically acceptable salt thereof; where R¹ is halogen, nitro, amino, C₁₋₄ alkylamino, C₁₋₄ alkanoylamino or C₁₋₄ alkyl;R² is halogen, nitro, amino, C₁₋₄ alkylamino, C₁₋₄ alkanoylamino, C₁₋₄ alkyl or C₃₋₄ alkoxy; provided that R¹ and R² are not both selected from amino, C₁₋₄ alkylamino, C₁₋₄ alkanoylamino and nitro; R³ is a C₁₋₃ alkylene group; and R⁴ is a pyridone group in which the nitrogen atom is optionally substituted with a group R⁵, where R⁵ is C₁₋₄ alkyl, hydroxy C₁₋₄ alkyl, C₁₋₄ alkoxy C₁₋₄ alkyl, or phenyl-C₁₋₄ alkyl optionally substituted by one hydroxy, halogen, C₁₋₄ alkoxy or C₁₋₄ alkyl; or is a 2- or 4- C₁₋₄ alkoxy pyridyl group.
 2. A compound according to claim 1, where R¹ is halogen.
 3. A compound according to claim 2, where R¹ is bromine.
 4. A compound according to claim 1, where R² is C₁₋₄ alkyl.
 5. A compound according to claim 4, where R² is methyl.
 6. A compound according to claim 1, where R² is amino.
 7. A compound according to claim 1 where R⁴ is 2-oxopyrid-4-yl.
 8. A compound according to claim 1, where R⁵ is methyl, ethyl, n-propyl or n-butyl.
 9. A compound according to claim 1, where R⁵ is methoxyethyl, ethoxyethyl or methoxypropyl.
 10. A compound according to claim 1 where R⁵ is optionally substituted phenyl C₁₋₄ alkyl where the optional substituent is hydroxy, halogen, C₁₋₄ alkoxy or C₁₋₄ alkyl.
 11. A compound according to claim 10, where R⁵ is benzyl, 2-phenylethyl, 3-phenylpropyl, 4-hydroxybenzyl, 2-(4-hydroxyphenyl)ethyl, 3-(4-hydroxyphenyl)propyl, 4-methoxybenzyl, 2-(4-methoxyphenyl)ethyl, 3-(4-methoxyphenyl)propyl, 4-chlorobenzyl, 2-(4-chlorophenyl)ethyl, 4-methylbenzyl, 2-(4-methylphenyl)ethyl and 3-(4-methylphenyl)propyl.
 12. A compound according to claim 1 which is 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[1-methyl-2-oxopyrid-4-ylmethyl]-4-pyrimidone or a pharmaceutically acceptable salt thereof.
 13. A compound according to claim 1 which is 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-1-benzyl-2-oxopyrid-4-ylmethyl]-4-pyrimidone or a pharmaceutically acceptable salt thereof.
 14. A compound according to claim 1 which is 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[1-[H]-2-oxopyrid-4-ylmethyl]-4-pyrimidone or a pharmaceutically acceptable salt thereof.
 15. A compound according to claim 1 which is 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[1- (2-phenylethyl)-2-oxopyrid-4-ylmethyl]-4-pyrimidone or a pharmaceutically acceptable salt thereof.
 16. A compound according to claim 1 which is 2-[4-(5-Bromo-3-methylpyrid-2-yl)butylamino]-5-[1-(2-(4-hydroxyphenyl)ethyl)-2-oxopyrid-4-ylmethyl]-4-pyrimidone or a pharmaceutically acceptable salt thereof.
 17. A compound according to claim 1 which is 2-[4-(5-bromo-3-aminopyrid-2-yl)butylamino]-5-[1-n-butyl-2-oxopyrid-4-ylmethyl]-4-pyrimidone or a pharmaceutically acceptable salt thereof.
 18. A hydrochloride salt of a compound of formula (2) according to claim
 1. 19. A pharmaceutical composition having histamine H₁ -antagonist activity comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
 20. A method of blocking histamine H₁ -receptors which comprises administering to a subject an effective amount to block said receptors of a compound according to claim
 1. 